This application for R21 support investigates bone loss caused by highly active antiretroviral therapy (HAART) in HIV-infected individuals. Although prevalences of osteopenia and osteoporosis are increased in HAART-naive HIV patients vs. age-matched, seronegative adults, HAART causes further bone loss. Men receiving protease inhibitors have a 2.2 fold higher prevalence of osteopenia than do HAART-naive HIV patients. Although studies are yet to demonstrate increased fracture rates in HIV patients (HAART-treated or not), the relative youth of HIV-infected individuals, and the dramatically increased life expectancy afforded by HAART, give rise to considerable concern about a possible fracture epidemic in the future. The etiology of bone loss in HIV remains poorly understood but risk factors include cytokine activation, hypogonadism, malnutrition, physical inactivity, intestinal malabsorption and weight loss. Given prior reports of acid-induced bone loss, diarrhea-induced and HAART-induced metabolic acid loading also deserve consideration. In humans and animals, metabolic acid loads induced by NH4C1 result in hypercalciuria and negative calcium balance; recent studies by our group show that reductions in dietary protein-induced acid loads decrease both urine calcium and bone resorption. These observations are potentially explained by invoking the notion of a skeletal buffer (consisting of alkaline salts of calcium) which is mobilized, at the expense of the skeleton, in defense of pH homeostasis. In this R21 grant submission, we hypothesize that bone loss in HIV patients results partly from large metabolic acid loads due to (a) bicarbonate wasting from diarrhea and (b) lactic acidemia / lactic acid burdens from HAART. We also predict that orally administered KHCO3 buffer will mitigate acid-induced bone resorption and will reduce bone loss. We will initially perform a cross-sectional analysis on 130 HIV-infected adults to assess the correlation between metabolic acid loads and skeletal remodelling. We will then stratify 90 ethnically diverse, acidemic HIV patients (serum HCO3 <24 mEq/L) into those taking and not taking HAART, and will then independently randomize each group to take placebo (2 weeks) followed by one of KHCO3, KC1, or placebo (2 additional weeks). Blood and urine will be collected weekly to assess (a) the magnitude of metabolic acid burdens (net renal acid excretion) in HIV patients, (b) urine calcium and bone resorption markers, and (c) whether exogenous KHCO3 mitigates calciuria and bone resorption (vs KC1 and placebo controls). Lastly, we will examine whether chronic KHCO3 retards bone loss (assessed by serial bone densitometry) in HIV patients randomized to KHCO3 or placebo. If successful, these exploratory "R21" studies could provide the basis for a novel approach to ameliorating bone loss in HAART-treated and HAART-naive patients.